Process to form a tablet and apparatus suitable for applying this process

ABSTRACT

The present invention pertains to a process for the preparation of a fast-disintegrating tablet ( 30 ) containing a medicinal substance, comprising the steps of providing a fluid formulation comprising the medicinal substance, providing a solid element ( 100 ) having formed therein at least one cavity, ( 101 ) cooling the solid element ( 100 ) to a temperature below a freezing temperature of the formulation, filling the cavity with the fluid formulation, solidifying the formulation while present in the cavity ( 101 ) to form a solid pellet comprising the medicinal substance without actively shaping the entire surface of the pellet, taking the pellet out of the cavity and drying the pellet in a vacuum to obtain the tablet. The invention also pertains to a system for performing such a process and a package containing the resulting tablet.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage entry under 35 U.S.C. 371 ofPCT/EP2010/055679, filed on Apr. 28, 2010, which claims priority to U.S.Provisional Application No. 61/173,631, filed on Apr. 29, 2009, and EPApplication No. 09159040.6, filed on Apr. 29, 2009. The content ofPCT/EP2010/055679 is hereby incorporated by reference in its entirety.

GENERAL FIELD OF THE INVENTION

The present invention pertains to a process for the preparation of afast-disintegrating tablet containing a medicinal substance.

BACKGROUND OF THE INVENTION

A process for the preparation of fast-disintegrating tablets (in thisspecification also denoted as “disintegrating tablets”) is known i.a.from U.S. Pat. No. 5,384,124 assigned to Farmalyoc. In the known processa paste comprising one or more medicinal substances is formed, whichpaste is mechanically divided into unitary doses having a well definedshape and volume, by distributing the paste in cavities of predeterminedshape and size, which cavities are present in a polyvinyl chloridecarrier element. After distributing the paste, the carrier element isput in a lyophiliser and the paste is freeze-dried. This way, eachunitary dose is formed into a tablet. The advantage of the freeze-dryingprocess is not only that the medicinal substance is brought in a verystable form, but also that a solid dosage form is obtained thatdisintegrates upon contact with a liquid. In particularly, if the pasteoriginally was based on water as the carrying solvent (the term“solvent” includes any liquid medium may serve as a carrier for othersubstances), such a tablet will normally disintegrate upon contact withwater. Such a dosage form is for example particularly suitable fortablets that have to disintegrate fast when taken orally (e.g. tabletscontaining medicinal substances that lose their activity when passingthe gastric channel), or for tablets that are used to in situ constitutea medicine for oral or parenteral administration (i.e. at the site ofadministration, immediately preceding the actual administration).

A variety of medicinal substances and/or combinations thereof can beused as the active ingredient in a fast disintegrating tablet, such asfor example analgesics and anti-inflammatory agents, antacids,anthelmintics, anti-arrhythmic agents, anti-bacterial agents,anti-coagulants, anti-depressants, anti-diabetics, anti-diarrheals,anti-epileptics, anti-fungal agents, anti-gout agents, anti-histamines,anti-hypertensive agents, anti-malarials, anti-migraine agents,anti-muscarinic agents, anti-neoplastic agents and immunosurpressants,anti-psychotics, anti-protozoal agents, anti-rheumatics, anti-thyroidagents, anti-viral agents, anxiolytics, sedatives, hypnotics andneuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids,cough suppressants, cytotoxics, decongestants, diuretics, enzymes,anti-parkinson agents, gastro-intestinal agents, histamine receptorantagonists, lipid regulating agents, local anaesthetics, neuromuscularagents, nitrates and anti-anginal agents, opioid analgesics, proteins,peptides, recombinant drugs, sex hormones, contraceptives, spermicides,stimulants etc.

The known method is being widely used in the life-sciences industry (seefor example “Orally disintegrating tablets: an overview of melt-mouthtablet technologies and techniques” by Deepak Kaushik, Harish Dureja andT. R. Saini, Maharishi Dayanand University and Shri G. S. Institute ofTechnology and Science, as published in “Tablets and Capsules”, 30 Jul.2004). In particular technologies such as Zydis (Catalent PharmaSolutions, Somerset, N.J., USA) and Lyoc (Laboratoires Farmalyoc,Maisons-Alfort, France) use this known process. Typically the startingpaste or fluid formulation is prepared and dosed into a preformedblister pack. This pack, i.e. the material present in the pack, is thenfrozen and subjected to freeze-drying to remove water. The resultantstructures are inherently very porous and rapidly disintegrate when theycontact saliva.

Indeed, the known method is very advantageous in that tablets can bemade that very rapidly disintegrate (which tablets are also known asFast-Melting Tablets, or FMT's), show improved pharmacokineticcharacteristics when compared with reference oral solid formulations,increased bioavailability, show improved patient compliance andside-effect reduction (see “Fast-Melting Tablets: Developments andTechnologies” by Luca Dobetti, in Pharmaceutical Technology DrugDelivery, 2001, pp 44-50). Known disadvantages are that the tablets havea relatively poor mechanical stability and high cost of production.These disadvantages however are believed to be inherent due to thefreeze-dry process used: Freeze-drying needs expensive equipment andinherently leads to mechanically less stable tablets when compared e.g.to traditional compression techniques. Due to this fact, the knownprocess takes place by using the final tablet package (i.e. the blisterpackage) as a carrier throughout the complete process. This inherentlymeans that each production step has to be adjusted such that it can beused in conjunction with this particular package. This limits thefreedom of operation in the various manufacturing steps and thusincreases cost price even further. However, given the advantages offreeze-dried products as disintegrating tablets, the inherent high costprice of the manufacturing process is accepted by the manufacturingpractitioner.

It is noted that other methods to arrive at fast-disintegrating tabletsare known from the prior art. For example, WO 93/12770 and US2006/0057207 (both assigned to Pfizer Inc.) describe a method whereinthe tablets are actively shaped over substantially their entire surfaceby compressing the frozen pellets in a closed mould. This known methodthus defers from passively obtaining a tablet shape, for example byusing a passively arrived shape that occurs through the mere action ofgravity and surface tension. This way a predetermined shape can bearrived at easily in a controlled manner. This method however isdisadvantageous in that it requires a rather complex die-and-punchassembly that is prone to leakage of the fluid formulation from thecavity (i.e. the closed mould). Also, frozen pellets tend to stick toeither the die or punch due to the use of compression forces. Anadvantage indeed is that by compressing the frozen pellet, goodmechanical properties are obtained which allow the frozen pellet to betaken out of the cavity integrally.

From WO 97/48383, U.S. Pat. No. 5,382,437 and EP 0 450 141 other methodsare known wherein the fluid formulation is brought over into opencavities of a solid element which is at room temperature, whereafterthis element is brought over in a freezer, typically for 30-60 minutes.This appears to be advantageous since the fluid formulation namely willnicely fill the cavity, thus leading to a frozen pellet of a size andshape that exactly corresponds to the size and shape of the cavity, andthus leading to a predictable pellet form. Disadvantages however arethat a cooling-heating cycle has to take place with this method and alsothat the entire process is relatively slow. Also, there is a risk ofloosing fluid from the cavity upon filling them with the (low viscosity)fluid formulation.

SUMMARY OF THE INVENTION

It is an object of the present invention to arrive at a process forobtaining a fast-disintegrating tablet using freeze-drying as a basictechnology, which has a significantly reduced cost price per tablet,while at the same time having excellent disintegration properties. Tothis end a process according to the General Field Of The Invention asmentioned here-above has been devised comprising the steps of providinga fluid formulation comprising the medicinal substance, providing asolid element having formed therein at least one cavity, cooling thesolid element to a temperature below a freezing temperature of theformulation, filling the cavity with the fluid formulation, solidifyingthe formulation while present in the cavity to form a solid pelletcomprising the medicinal substance without actively shaping the entiresurface of the pellet, taking the pellet out of the cavity, and dryingthe pellet in a vacuum to obtain the tablet. Applicant surprisinglyfound that the advantages of the known method can be preserved, while atthe same time significantly increasing the freedom in the manufacturingprocess, and thus enabling a significant decrease the cost price pertablet, by firstly filling an open cavity with a fluid formulationcomprising the medicinal substance (which also covers filling the cavitywith two or more separate sub-formulations which together form the fluidformulation containing the medicinal substance) and then freezing thefluid formulation in that cavity to form a solid pellet by simplyleaving the fluid formulation in the pre-cooled cavity, not applying anyactive shaping tools such that one may end up with an uncompressedfrozen pellet having a shape (at the open end of the cavity) that isformed merely by gravitational forces and surface tension (a meniscus),taking the frozen pellet out of the cavity, and after that drying thepellet (for example in a lyophilising apparatus). It was also found thatit is particularly advantageous to have the solid element at atemperature below the freezing temperature of the formulation uponfilling the cavity. At first glance this seems a disadvantage: The fluidformulation namely will start to solidify immediately upon contact withthe cavity wall, theoretically leading to a frozen pellet of a size andshape that does not correspond to the size and shape of the cavity, thusleading to an uncontrolled freezing process and thus an unpredictablepellet form. However, applicant found that for a temperature below thefreezing temperature of the fluid formulation a filling speed can befound that is fast enough to counterbalance the immediate freezing ofthe fluid, simply because the amount of heat present in the flow offluid formulation may simply counterbalance the extraction of heat bythe cold solid element, or at least an adequate part of the heatextraction. Overall, the new process is easier to control: thetemperature of the solid element can be kept at the same level, whereasa cooling-heating cycle has to take place with prior art methods.Moreover, the process is faster. Heat is already being extracted uponfilling the cavity. Also, there is less risk of loosing fluid from thecavity, since the fluid will cool down very fast after entry of thecavity and thus will immediately show an increased viscosity.

In this new process the final tablet package does not need to beinvolved in any of the process steps. Therefore, not only a standardcheap package may be used, but also, each of the manufacturing steps cantake place with tools optimised for their task. With the prior artprocess for example, where a blister package is used as the carrier forthe tablets in a lyophiliser, the drying circumstances have to beadjusted to the relatively low amount of heat that can be transferredthrough the (plastic) package. This may significantly increase thethermal load (for example a high local temperature) on each tabletduring the drying step and also may significantly increase the necessaryprocess time.

Another major advantage of the present method is that the tablets in thefinished packed product are not present in the mould in which they havebeen formed. With the prior art method as known from i.a. U.S. Pat. No.5,384,124 the pellets are formed in the blister package which serves asa mould. The pellets however stay in their moulds during the completeprocess, until they are transformed into tablets present in theirfinished packaging. Therefore there is a high risk that the tablets moreor less stick to the blister wall and can only be removed by applyingconsiderable mechanical forces. This, in combination with the fact thatfreeze-dried tablets are inherently not too stable (when compared toclassic compressed tablets) often results in tablets being broken evenbefore they can be administered. This may lead to tablets not being usedor too little active ingredient being administered to a patient.

Another important advantage of the present process is that the freezingstep does not need to take place in the lyophiliser itself. In theprocess known from U.S. Pat. No. 5,384,124 the freezing step takes placein the lyophiliser since the paste is present in the blister packageanyway. However, in the known process, extracting heat from the paste tofreeze it takes a relatively long time. In the present method, bysolidifying the fluid formulation in a separate step in a dedicatedcavity, and thereafter taking the frozen pellet out of the cavity andsubject it to a lyophilising action in an additional step, the initialfreezing can be done significantly more efficiently.

Yet another substantial advantage of the present invention is that thestep of obtaining the solid frozen pellets does not depend on theavailable drying capacity. Since the provision of the frozen pellets iscompletely independent of the drying step, the pellets can be producedseparately and for example stored until drying capacity comes available.In particular when the medicinal substance is of biological origin, itis important that a batch of fluid formulation containing this substancecan be completely processed into frozen pellets, independently from thecurrently available drying capacity.

With regard to the die-and-punch methods as known from the prior art,the present method has the important advantage that it does not sufferfrom leakage of the fluid formulation from the cavity. Since the fluidformulation is simply left to freeze in the open cavity without activelyshaping the entire surface of the pellet by applying e.g. compressionforces or other active moulding techniques that shape the surface of thepellet, there is no risk of fluid formulation being pressed out of thecavity. Also, there is a significantly decreased risk of the pelletsticking to any of the parts used for actively shaping the pellet.Surprisingly it appeared that by simply leaving the fluid formulation tofreeze, without applying any compression forces, the pellet still mayhave sufficient mechanical strength to be taken out of the cavity forfurther processing such as lyophilising.

The present invention is based on several recognitions, the first onebeing that the finished freeze-dried product may be mechanically not toostable, but the intermediate frozen product surprisingly does not sufferfrom this disadvantage despite the fact that this frozen product is notcompressed. This opens possibilities for additional mechanical handlingof the intermediate pellet. However, such handling in the knownFarmalyoc process makes no sense, since the frozen pellet is alreadypresent in the lyophiliser in its final blister package. Applicanthowever came to a second insight, namely that the drying step in thisknown process is very inefficient mainly due to the fact that when usingthe final tablet package as a carrier in the lyophiliser, the dryingspace is not adequately used (each tablet takes a relatively largeamount of space since the tablets cannot be in a contiguous relation inthe package). This inefficient use of the lyophiliser in the knownprocess is inherent, but can be overcome by separating the freezing anddrying step by using a carrier for the freezing step that differs fromthe carrier used in the drying step.

It is noted that the present invention also pertains to a system forperforming a process as described here-above, comprising an elementprovided with multiple cavities, a filling unit for filling each cavitywith a fluid formulation comprising a medicinal substance, a coolingunit for cooling the element below a freezing temperature of theformulation such that a solid pellet comprising the medicinal substancecan be formed in each cavity upon freezing of the fluid formulation, apushing element for pushing the pellets out of their respective cavity,and a chamber for drying the pellets in a vacuum to form tablets thatdisintegrate upon contact with a liquid.

The invention also pertains to a package (i.e. an air and water-tightpacked product which can be used for commercial activities such a salesto an end-user) comprising a container having therein at least onefast-disintegrating tablet containing a medicinal substance, wherein thetablet is formed in a cavity using a method according to the presentinvention, the cavity being different from the container in which thetablet is packed. As described here-above, a major advantage of thepresent invention is that tablets in the finished packed product are notpresent in the mould in which they have been formed, which almostexcludes the chance of a tablet sticking to its blister in the finishedpackage. This near exclusion improves the convenience of handling thetablets by a physician, DVM, patient or the like. The container can forexample be a cup with a lid, a vial, a syringe, a blister with apeel-off or push-through strip etc.

DEFINITIONS

A tablet is a solid dosage form, for example for direct oral, rectal orparenteral administration or for indirect administration for exampleafter mixture with a carrier material, in particular a liquid, foradministration in a dissolved or dispersed form. A tablet can bedistinguished from powder or fine granules in that a tablet can beindividually manually handled. A minimum length size of a tablet is 1mm, preferably 2 mm, more preferably 4 mm and typically (but notnecessarily) between 4 and 20 mm.

An orally disintegrating tablet is a freeze-dried tablet thatdisintegrates upon contact with saliva, for example in the oral cavity,within 60 seconds, preferably within 30 seconds, more preferably within10 seconds.

Freeze-drying or lyophilisation is a process used in the creation of astable preparation of a substance by freezing a fluid formulationcontaining the substance and substantially remove the frozen liquidunder vacuum.

A vacuum is air or other gas at a reduced (sub-atmospheric) pressure.

To disintegrate is to lose unity and be reduced to fragments. The term“disintegrate” covers dissolution (having fragments at molecular level).

Fast-disintegration means disintegration which starts upon contact witha liquid, in particular water at 37° C., and is completed within 60seconds, preferably within 30 seconds, more preferably within 10seconds.

A medicinal substance is any substance that can be used to treat adisease or disorder, i.e. to aid in preventing, ameliorating or curingthe disease or disorder. Such a substance may for example be a chemicalor biological compound, such as a natural or synthetic peptide orprotein, a (poly-)saccharide or any other organic or inorganic molecule,a dead or alive micro-organism, a dead or alive parasite etc.

A freezing temperature of a fluid formulation is a temperature at whichthe consistency of the formulation transforms from liquid to solid, i.e.a consistency which can withstand an external force without a change ofform.

A heat conducting material is a material having a heat transfercoefficient of at least 1 W/mK (Watt per meter Kelvin).

Abhesive means the capability of resisting adhesion.

A crystalline material is a material that can form crystals uponsolidification under equilibrium conditions.

A gelator is an agent that is capable of forming a network of moleculeswithin a fluid to provide the fluid the consistency of a gel, i.e.having at least some self-supporting capacity (not being a free-flowingliquid under all circumstances). The term gelator also covers an agentcomprising two or more different compounds or materials that each arecapable of forming a network of molecules within a fluid.

EMBODIMENTS OF THE INVENTION

In an embodiment of the process according to the invention theformulation is cooled by extracting heat from the formulation through acavity wall by conduction. This means that at least the main part (morethan 50%) of the heat that is to be extracted to freeze the formulation,is extracted by conduction through the cavity wall. Preferably more than80% up to virtually 100% of the heat is extracted by conduction throughthe cavity wall. In the known processes nearly all of the heat isextracted by convection, in particular using nitrogen gas that travelsaround the fluid formulation to extract heat until the formulation issolidified and has transformed into a frozen pellet. Although convectioncan be adequately used to freeze the fluid formulation, applicant foundthat when conduction is used, by having a heat conducting materialaround at least part of the fluid formulation, the cooling process mayprovide a pellet with advantageous mechanical stability, for example anadequate mechanical strength and/or low friability, while maintainingits fast disintegrating properties at an adequate level. The reason forthis is not clear but may be due to the fact that extraction of heat byconduction provides a more efficient and thus significantly fastercooling process, which leads to a different arrangement of theconstituting molecules in the pellet. It may very well be that asignificantly faster cooling process leads to a solidification processthat provides a more amorphous-like end-product, leading to a lessvulnerable end-product. Because of the noted effect, a tablet obtainedaccording to this embodiment of the present process is ideally suitablefor an orally disintegrating tablet (for administration to humans oranimals). Such a tablet ideally meets multiple demands, for examplesufficient mechanical strength for manual handling (to enable easyremoval of a tablet from a package and allow putting the tablet in themouth of a patient), optionally possess mucoadhesive properties (forexample such that a tablet will disintegrate in the mouth and not reachthe stomach), while not being sticky in order not to hamper handling ofthe tablet, having an acceptable taste, and providing a very rapiddisintegration (such that for example high blood levels of the medicinalsubstance can be obtained). The liquid formulation used for making thetablets may optionally contain additives such as for example surfactantsor other substances which can be used to give the final tabletproperties useful for the specific use of the tablet. Such substancesmay for example be colorants, sweeteners or other taste modifying ormasking agents, preservatives, colouring agents, pH modifiers or anyother substance that is compatible with the rest of the constituents ofthe tablet, and if necessary pharmaceutically acceptable for theintended patient.

It is noted that in the prior art methods, a small amount of heat may beextracted from the fluid formulation through the wall of the blister.This however does not qualify as heat extraction by conduction in thesense of the present invention since the blister package material is aplastic, which typically has a heat transfer coefficient of 0.1 to 0.2W/mK, which inevitably means that the main part of the heat is extractedby other means than conduction (viz. convection).

In an embodiment, the volume of the pellet is larger than a maximumvolume of a free droplet of the fluid formulation at a temperature andpressure used when filling the cavity. In this embodiment the pellet isbigger than a single free droplet of the fluid formulation. Thisembodiment is advantageous in obtaining tablets of a size that can beeasily handled manually, based on a fluid formulation of which onesingle free droplet would only be as large as for example 50 μl. Forexample, if the fluid formulation is based on water as a solvent(carrier fluid) than a single free droplet at a temperature of 20° C.and a pressure of 1 atmosphere is about 50 μl. After freezing and dryingsuch a droplet, the diameter will be about 2.3 mm. This is quite smallfor manual handling. It is preferred that larger tablets are made. Inthe prior art, this is accomplished by transforming the fluidformulation into a formulation such that droplets up to 1 ml can beobtained. For this however, all kinds of additives are required to givethe fluid formulation a gel-like consistency. These additives not onlymake the production process more complex, they must also be taken intoaccount when assessing compatibility with the subject patient, e.g. ahuman being or a pet. Although freezing one single droplet hasadvantages process wise, it was applicants merit to find out thatconstituting a pellet out of a volume that correspond to the volume ofmultiple single droplets, leads to less stringent conditions for theconstituents of the fluid formulation, simply because less compoundsneed to be present in the formulation.

In a further embodiment, the speed at which the cavity is filled withthe fluid formulation is chosen such that the surface of the part of thepellet that is in the cavity before the pellet is taken out of thiscavity, is in essence a negative print of the surface of the cavity. Itwas found that a filling speed can be chosen such that the surface ofthe pellet, at least the part that is contiguous to the cavity, is inessence a negative print of the surface of the cavity (in essencemeaning at least as far as visible with the naked human eye). When thefilling speed is below this speed, an uneven pellet surface will beformed since the fluid that enters the cavity will solidify before itcan completely wet the surface of the cavity. Complete wetting is foundparticularly suitable not only to form nice and smooth pellets and thustablets, but also, this gives the opportunity to form a logo or anyother identifying means in the tablet (for example a logo of thecommercial party bringing the tablet to the market or any otherimprint). For this, one needs to have a mirror image of the imprint inthe cavity wall (either positive, that is being applied on top of thewall, or negative, that is being indented in the wall).

In another embodiment a cross-section of the part of the pellet that isin the cavity is smaller than a cross-section of the cavity at itsentrance. In this embodiment the pellet can be easily removed from thecavity, for example by simply pushing or pulling the pellet out thecavity, using a mechanical force, air pressure, gravity etc.

In yet another embodiment the volume of the cavity is smaller than thevolume of the pellet. In the prior art methods, a cavity is chosen thatexactly corresponds to the size and shape of the tablet to be formed.Surprisingly however, applicant found that a cavity may be used that hasa volume smaller than that of the tablet to be formed. In thisembodiment the pellet projects from the surface of the element, out ofthe cavity. This is enabled i.a. since the fluid formulation is rapidlycooled by the conductive contact with the cold element. This helps toensure that a pellet can be formed that even sticks out of the cavity.An advantage of this particular embodiment is that the pellet can beremoved relatively easy from the cavity since the contact surfacebetween the pellet and cavity is small when compared to a pellet that iscompletely enclosed by or sunk in the cavity. Another advantage of thisembodiment is that there may be provided a discontinuity in the physicalappearance of the tablet corresponding to the transition site betweenthe cavity and the open space above the cavity. Since the pellet to beformed sticks out of the cavity, there may be provided a discontinuityin the shape of the pellet at the cavity entry. Such a discontinuity maybe used to distinguish the tablet from other tablets (thus being forexample an alternative for a company logo, icon or colour), or may beused to provide advantageous mechanical properties.

In a preferred embodiment, the volume of the cavity is smaller than 50%of the volume of the pellet. In this embodiment, more than half of thepellet sticks out of the element in which the cavity is formed. Thismakes removal of the pellet very easy. A minimum volume to ensure apractically adequate heat extraction from the fluid formulation is about15%, preferably about 20%.

In an embodiment, a measure is taken to support automatic detachment ofthe pellet from the cavity wall. Automatic detachment, i.e. withoutmechanical intervention of any kind, significantly reduces the chancesthat a pellet will be damaged upon removal from its correspondingcavity. In an embodiment wherein the cavity is formed in a solidelement, the automatic detachment is supported by keeping thetemperature of the solid element adequately beneath the freezingtemperature of the fluid formulation. It has been found that for everyfluid formulation, a temperature can be found which is that low, that itgenerates a speed of shrinkage of the pellet sufficient to induceautomatic detachment of the pellet from the cavity wall. For a waterbased fluid formulation, the temperature should be at least 80 degrees(K) below the freezing point of the formulation, thus about −80° C.Preferably the difference is about 100-120 degrees up to even 196degrees. The difference needed depends on the constitution of theformulation but can simply be found by increasing it from 0, untilautomatic detachment is provided. Such detachment can be recognisedeasily since upon automatic detachment, the pellet can be simply removedfrom the cavity using merely gravitational forces (turning the elementupside down). In another embodiment the automatic detachment issupported by providing the cavity wall with an abhesive surface bychemical and/or physical means. Commonly known chemical means forobtaining an abhesive surface are for example coatings with a highfluorine content (Teflon® for example) or high silicone content.Physical means are for example lotus leaf-like structures or commonlyknown nanopins. An abhesive surface has the additional advantage thatthe pellet can be formed in a very shallow cavity. However, adisadvantage is that complete wetting of the surface to form a negativeprint of the cavity wall is inherently difficult to achieve.

In an embodiment the pellet is taken out of the cavity by applying apushing force to the pellet. It has been found that applying a pushingforce, despite inherent risk of mechanically damaging the frozen pellet,provides excellent results with regard to removing a pellet from thecavity while keeping its shape intact. The advantage of a pushing forceover for example a stream of blowing gas is that pushing can be donewith a clean mechanical element, while a stream of air has inherentsterility problems. In a preferred embodiment the pellet is pushed outof the cavity using a tangentially directed force. It was found that atangential force, although less direct, has the advantage that there isless mechanical impact on the pellet, while even improving the removalprocess. By applying a tangential force, the pellet can start to twistand turn in its cavity which will lead to easy and reliable removalwithout damaging the pellet.

In an embodiment multiple pellets are placed in a packed bed before thepellets are dried in the vacuum. In this embodiment the pellets are notdried while arranged in a single layer, but are packed to be part of amultiple layer bed. This way the drying step, which may take place in alyophiliser, is operated at a significantly higher efficiency. However,since the drying process depends inter alia on heat transfer through thebed, the number of layers will be restricted to 2 or 3. In a furtherembodiment therefore, the pellets are packed in a heat conductingcontainer having a bottom and side walls, and a heat source is providedabove a top layer of the packed pellets, the heat source having asurface directed to a top layer of the bed, which surface has anemissivity coefficient of at least 0.4, whereafter the pellets aresubjected to the vacuum while at the same time heating at least thebottom of the container and the said surface to provide heat to theparticles to support drying of the pellets. In this embodiment thenumber of layers in the bed can be increased to be over 3. Theemissivity coefficient (usually denoted as E) in this respect is theratio of energy radiated by the surface to energy radiated by a trueblack body of the same temperature. It is a measure of the ability toabsorb and radiate energy. A true black body would have an ε=1 while anyreal surface or object would have an ε<1. Emissivity is a numericalvalue and does not have units. By having an emissivity coefficient of atleast 0.4, the heated surface radiates relatively high quantities ofheat to the particles. Emissivity in the sense of the present inventionis the mean emissivity as established at four different temperatures ofthe surface, viz. 55, 60, 65 and 70° C. The emissivity can be measuredby using dedicated emissivity measurement equipment as commerciallyavailable such as the Model 205WB of Advanced Fuel Research Inc., EastHartford, Conn. USA. Such equipment however is very expensive.Alternatively, as commonly known, a very simple way of measuring theemissivity is to heat the surface and a surface with a known emissivityto the same temperature as determined by a thermocouple. Then read thetemperature of the two surfaces with a standard infrared pyrometer. Thedifference in the two infrared temperature measurements is due to thedifference in the emissivities of the surfaces (see also Applied Optics,Vol. 13, No 9, September 1974).

As mentioned here-above, an embodiment of the method according to thepresent invention is specifically advantageous for obtaining so calledorally disintegrating tablets (viz. the embodiment wherein theformulation is cooled by extracting heat from the formulation through acavity wall by conduction). In an embodiment of this specific process toobtain ODT's, the formulation comprises a crystalline carrier materialthat is solid at room temperature and a gelator. A crystalline carrierhas the advantage that it can be easy formulated into a fluidformulation, and that it provides good mechanical properties to thetablet. The gelator is incorporated to even further improve themechanical properties of the tablet. Examples of suitable carriermaterials are sugars such as mannitol, dextrose, lactose, galactose,trehalose and cyclic sugars such as cyclodextrin, inorganic salts suchas sodium phosphate, sodium chloride and aluminium silicates, aminoacids typically having from 2 to 12 carbon atoms such as glycine,L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline,L-isoleucine, L-leucine and L-phenylalanine. The gelator may be anyagent that is capable of forming a network of molecules within a fluidto provide the fluid the consistency of a gel. Such an agent maycomprise high molecular proteins or other polymers but may also be basedon small molecules that can form networks through recombination of thesmall molecules into long chains (as known i.a. from U.S. Pat. No.6,471,758). The gelator has the advantage that the large moleculesprovide additional mechanical stability to the final tablet. Typicalexamples of gelators are gelatins, dextrins and soy-, wheat- andpsyllium seed proteins, gums such as guar, agar, acacia, xanthan andcarreagenan, polysachharides, alginates, carboxymethylcelluloses,pectins, polyvinylpyrrolidone etc.

In a further embodiment the formulation comprises 3 or more weightpercent of the crystalline material and about 4 weight percent of thegelator. Typically the amount of a crystalline carrier material in aformulation to obtain an ODT is kept below 3 weight percent. For thegelator an amount of about 4 weight percent is used. Applicant foundthat when using 3 or more weight percent of the crystalline carrier andat the same time using about 4 weight percent of the gelator,surprisingly leads to a high mechanical strength of the final tablet incombination with very good disintegration properties.

In an embodiment the gelator comprises a non gel-forming material,preferably a collagen derived material, such as a gelatine. A nongel-forming material is a material that at a concentration of 4% (w/w)in a fluid formulation (in particular water), at a temperature at whichthat fluid formulation is used for dosing purposes (in the present casefor filling cavities at room temperature, 20° C.), does not form a gelin the said fluid formulation when left in a stationary situation for 24hours. Although the gelator in principle is capable of forming a gel ina liquid, we found that it is advantageous to choose a gelator that not,or at least not completely, forms a gel in the liquid formulation whenfilling the cavity (this can be simply accomplished by choosing agelator that dissolves in the fluid formulation at the said temperaturein stead of forming a network of gelator molecules in the fluid). Thissimplifies the dosing of the fluid formulation, given the less highviscosity and/or the less non-Newtonian behaviour of the fluidformulation. After dosing, upon lowering the temperature the gelatorwill form a gel. In a preferred embodiment the collagen derived materialis a gelatin having a weight average molecular weight of 2×10⁴ g/mol(thus having an actual average weight between 15.000 and 25.000 g/mol).Applicant found that the use of such a gelator may lead to less stickytablets, and also, to tablets having very good disintegration propertieswhile keeping adequate mechanical strength despite the relatively lowmolecular weight of the gelator. Gelati Sol P (Gelita, Eberbach,Germany) is a good example of such a gelator.

SPECIFIC EXAMPLES OF THE INVENTION

The invention will now be explained in more detail used the followingnon-limiting examples

FIG. 1 schematically shows a cavity tray and corresponding coolingelement for use in a method to obtain frozen pellets

FIG. 2 schematically shows the basic parts of an apparatus for obtainingfrozen pellets

FIG. 3 is a schematic top plan view of parts of the apparatus asdepicted in FIG. 2

FIG. 4 schematically depicts a filling needle in conjunction with thecorresponding cavity

FIG. 5 schematically shows a drying chamber for use in the presentmethod and system

FIG. 6 schematically shows a tensile tester for establishing thecrushing strength of a tablet

FIG. 7 schematically shows a package containing a tablet according tothe invention

FIG. 8 schematically shows a device to measure the stability of tabletswhen being pressed through a foil.

FIG. 9 schematically shows examples of tablets being pressed through afoil.

Example 1 Obtaining tablets with a vaccine component

Example 2 Obtaining tablets containing a chemical drug

Example 3 Establishing the mechanical stability of a tablet

Example 4 Alternative way of establishing the mechanical stability of anODT

FIG. 1

FIG. 1A schematically shows a cavity tray 100 and corresponding coolingelement 105 for use in a method to obtain frozen pellets. Cavity tray100 is a solid steel plate (made of stainless steel, grade 316L) havinga thickness of 6 mm. In the plate three rows (102, 103 and 104) ofcavities 101 are formed. FIG. 1B gives an example of a first type ofcavity. The shown cavity 101 has a spherical shape, a radius r of 2.9 mmand a depth d of 2.1 mm. In such a cavity, a spherical pellet 30 with avolume of about 100 μl (having a radius of about 2.9 mm) can be formed.Another example, which can be used for larger tablets, is shown in FIG.1B. This cavity 101′ is also spherical, has a radius r of 4.9 mm and adepth of 4.0 mm. In such a cavity a spherical pellet 30′ with a volumeof about 500 μl (having a radius of about 4.9 mm) can be formed. Indeed,other sizes (for example between 50 μl and 1000 μl) and shapes can alsobe provided for, for example to obtain an oblate (also known as “M&M-”or “Smartie-” shaped) pellet, an egg-shaped pellet, an oval(zeppelin-shaped) pellet etc. In particular, an oblate pellet can beformed in an oblate cavity having a length and width of 6.0 mm and adepth of 3.3 mm by dosing a volume of about 300 μl.

Tray 100 rests under gravitational forces on cooling element 105 (in analternative embodiment, the tray can be clamped to cooling element 105).This element is a hollow stainless steel box, having a height of about 6cm. The box 105 has an entrance 106 and an outlet 107. Through theentrance 106, liquid nitrogen can be supplied (indicated by the arrow A)at a temperature of about −196° C. At the outlet 107 nitrogen (a mixtureof liquid and gas) leaves the box 105 (indicated by the arrow B). Thisway the tray 100 can be cooled adequately to obtain a very fastsolidification process when a fluid formulation is dispensed in one (ormore) of the cavities 101. Depending i.a. on the temperature of thefluid formulation, the temperature of the surrounding air, the nitrogenflow and the speed at which solid pellets are produced, an equilibriumtemperature of between −85° C. and −145° C. for the tray 100 can beobtained in the shown arrangement.

FIG. 2

FIG. 2 schematically shows the basic parts of an apparatus for obtainingfrozen pellets. The same tray 100 and cooling element 105 as depicted inFIG. 1 can be seen. At the front (downstream of the tray 100) a blackplastic container 15 is shown, which container has handles 16 formanually handling the container. This container 15 is placed directlyagainst cooling element 105. The container is cooled to a temperature ofabout −45° C. by having its support (not shown) cooled by using liquidnitrogen. At the other side of the tray 100 (upstream side) a collectingelement 120 is shown, which element is divided into three compartments121, 122 and 123. This element travels over the surface of tray 100(with a space of about 0.2 mm between the bottom of element 120 and thesurface of tray 100) in the direction C and pushes frozen pellets out oftheir cavities. These pellets are then collected in each of thecompartments 121, 122 and 123 and are ultimately brought over intocontainer 15. Attached to collecting element 120, via brackets 131, isdispensing unit 130. This unit comprises three needles 132, 133 and 134,corresponding to cavity rows 102, 103 and 104 respectively. The needlesare used to dispense the fluid formulation in each of the cavities. Thefluid formulation is supplied to each of the needles via tubes 152, 153and 154 respectively.

When operating the device, the atmosphere is cooled to a temperature ofaround 15° C. using dry nitrogen gas. Because of this relatively hightemperature of the surrounding atmosphere, a water based fluidformulation can be handled in and around the apparatus without the riskthat the formulation freezes in the tubes 152, 153, 154 or the needles132, 133 an 134. Dry nitrogen gas is used to prevent crystallization ofwater into ice on the various parts that are kept below 0° C. In thissetup, the tray 100 will have an equilibrium temperature of about −125°C. The collecting element 120 has a temperature around −35° C., and thecontainer 15 will have a temperature of about −45° C.

The process starts with moving the element 120 in the direction C untilthe needles coincide with the first (upstream) cavities. Then themovement of element 120 is temporarily stopped, and the first threecavities are filled with fluid formulation. When finished, the element120 moves forward until the needles coincide with the next threecavities. Then, these cavities are filled with fluid formulation. Thisprocess continues till all cavities are filled with the fluidformulation. Then the element 120 is lifted somewhat (about 25 mm) andbrought back to its original position at the upstream part of the tray100. Then the element 120 travels forward again in the shown directionC. This time, the element will come across frozen pellets in each of thecavities. The pellets are pushed out of their cavities and collecting inthe compartments 121, 122 and 123 respectively. In this process, eachpellet may remain between 20 and 90 seconds in its cavity (from fillinguntil pushing out, depending i.a. on the size of the pellet: the largerthe pellet, the longer the solidification process will take). At thesame time, upstream of element 120, the emptied cavities are refilled asdescribed here-above. This process continues until container 15 isadequately filled with frozen pellets.

FIG. 3

FIG. 3 is a schematic top plan view of parts of the apparatus asdepicted in FIG. 2. In this schematic view, the inner arrangement ofcollecting element 120 is shown. Each compartment 121, 122 and 123comprises an inner slanted wall 141, 142 and 143 respectively. Each ofthese walls is slanted with respect to moving direction C with an angleof 10°. The walls hit the frozen pellets and push them out of theircavities. Since each wall is slanted, the pellets are pushed out with atangentially directed force. This has the advantage that the pellets aremore or less twisted out of their cavities. It has appeared that thissignificantly reduces the risk of pellets being damaged. When they arepushed out, the pellets are collected at the back of the compartments,in this case in roundings 161, 162 and 163 respectively. At thedownstream position of the element 120 (adjacent container 15) thepellets will automatically fall into container 15.

FIG. 4

FIG. 4 schematically depicts a filling needle in conjunction with thecorresponding cavity. The needle 132 has a tip 232. This tip 232 isarranged to have a vertical position with respect to the surface of tray100, such that the tip coincides with the uppermost part of the pellet30 to be formed in cavity 101. From this position, the cavity is filledwith fluid formulation. The speed of filling can be tuned to obtain anydesired filling process. For example, when a very low speed is chosen, arather irregular shaped pellet will be formed, i.a. since the fluid willnot be able to completely wet the cavity wall. When a sufficiently highspeed is chosen a complete wetting can be achieved. This speed dependsi.a. on the actual temperature of the fluid at the time of filling thecavity, the cavity wall temperature, the viscosity of the fluid etc. Foreach formulation this speed can be found by performing routineexperiments. After the required amount of fluid formulation is filled,the needle travels further to the next cavity. However, it is preferredthat a waiting time, for example about 0.1 seconds, is used between themoment when all formulation has been dispensed and the moment at whichthe needle starts traveling again. This may prevent mechanicallydisturbing the dosed pellet. It is noted that in this particular examplea spherical pellet 30 is depicted. However, other shapes can also beformed. In any case, the optimal position for the tip is right at theuppermost part of the pellet to be formed.

FIG. 5

In FIG. 5 a lyophiliser (freeze-dry apparatus) is schematicallydepicted. Such a lyophiliser could for example be the Christ Epsilon2-12D as available from Salmen Kipp, Breukelen, The Netherlands. Thelyophiliser 1 comprises a housing 2 and multiple shelves 3. The Epsilon2-12D comprises 4+1 shelves, for matters of convenience three of theseshelves (viz. shelves 3 a, 3 b and 3 c) are shown in FIG. 1. Each ofthese shelves is provided with a heating element 5 (referred to withnumerals 5 a, 5 b and 5 c respectively) for even heating of the shelves3. The heating is controlled by making use of processing unit 10. Thehousing is connected to a pump unit 11 for providing adequate lowpressure within the housing 2. The interior of the housing can be cooledto a temperature as low as −60° C. by using cooling unit 12, inparticular containing a condenser (in fact, it is the condenser that iskept at about −60° C., which acts as a driving force for condensation ofsublimated ice). Shelves 3 a and 3 b are provided with black PTFE plates8 and 8′ fixed to their bottom. The emissivity coefficient of theseplates is 0.78. By intimate contact between these black plates and theshelves, these plates can be warmed virtually to the same temperature asthe shelves themselves. This way, the plates 8 can be regarded as heatsource in addition to the shelves 3 themselves.

Placed on the shelves are container 15 and 15′. These containers aremade of a heat conducting material, in this case carbon black filledpolyethyleneterephtalate. The containers are in a heat conductingcontact with the shelves on which they rest. In the shown arrangement,the containers are filled with frozen pellets 30 which thus form a bed29 of packed pellets in each container. By heating the shelves, theparticles may receive heat via the heated bottom and side walls of thecontainers and by irradiation from the heated plates 8 and 8′respectively. It is noted that each container 15 has a width and lengthof about 20 to 30 cm and a height of about 4 cm. The height of thepacked bed after filling the container is typically 1.5 to 3 cm. Thisleads to typical values for an aspect ratio of the bed of between 20/3≈7to about 30/1.5=20. However, monolayer arrangement of pellets can alsobe used.

FIG. 6

FIG. 6 schematically shows a tensile tester for establishing thecrushing strength of a tablet. This figure is a schematically side viewof a LR5K Plus tensile tester (available from Lloyd Instruments, UK),with a load cell 400, to test the crushing strength of a tablet 30. Forthis, the tablet 30 is being subjected to a load force with rod 401while it rests on support 300.

FIG. 7

In FIG. 7 a package 500 containing a tablet according to the inventionis schematically shown. Package 500 comprises a rectangular base andmultiple blisters 501 having contained therein tablets 30. The blisterpackage can be of the peel-off type, wherein a layer (not shown) fixedto the rectangular base can be peeled off to open each one of theblister to take the respective tablet out. Also, in particular when themechanical stability of the tablet is sufficient, the layer can be of amore conventional type (often aluminum foil) wherein each tablet ispushed through the layer.

FIG. 8

FIG. 8 schematically shows an alternative device to establish themechanical stability of an ODT. With this device the propensity offreeze dried tablets to remain intact after being pressed through afoil. Dies 3001 and 3002 are units that contain cylindrical holes of 13diameter. An aluminium foil 3005 with a thickness of 5 μm is placedbetween the dies and covered by a rubber ring 3003 to prevent movementof foil. A freeze dried tablet 30 is placed on the foil and can bepressed through the foil using a glass rod 4001 by exerting a manualforce on the rod. After pressing tablets through the foil, eithercomplete tablets or fragments of tablets can be collected below die3002.

FIG. 9

FIG. 9 shows examples of tablets or fragments of tablets afterperforming the test to measure the propensity to remain in tact afterbeing pressed through a foil. FIG. 9 a shows tablets 30 that remainintact when being pressed through a 5 μm foil. FIG. 9 b shows tablets30″ that are fragmented when being subjected to the same test.

Example 1

To obtain tablets for vaccine formulation, live virus was harvested fromeggs. The allantois fluid containing the virus (either IB or ND; seetable 2) was mixed with a stabilizer. The stabilizer is known fromWO2006/094974 A2, and in particular described in Table 5 of that patentapplication (with a glycine content of 160 g/l). The method of addingthe stabilizer is also described in that patent application, namely inthe general outline of the introductory part of the “Examples” sectionon page 24.

A plate is used having three rows of cavities according to FIG. 1B. Ineach of these cavities about 100 μl of fluid formulation is dispensed inapproximately 0.3 seconds. The formulation will start the freezeimmediately upon contacting the cavity wall. However, it takesapproximately 15 seconds before the pellet is substantially frozen suchthat it can be mechanically handled. After this, the pellets (which havea diameter of approximately 5.7 mm) are pushed out of the cavities (asexplained in conjunction with FIGS. 2 and 3) and transferred tofreeze-dry container 15.

The frozen pellets (having a temperature of about minus 45° C.) arearranged in the container 15 in the form of a packed bed with an aspectratio of about 15. Multiple containers are then put in the lyophiliser(see FIG. 5) which has beforehand been brought to a temperature of about−35° C. The lyophiliser is subjected to the following freeze-drye cycle(Table 1).

TABLE 1 Phase Time [h:m] Temp [° C.] Vacuum [mbar] Freezing 00:30 −351000 Preparation 00:20 −35 1000 Initial sublimation 00:10 −35 0.370Sublimation 1 03:00 40 0.370 Sublimation 2 16:00 40 0.370 Closing step00:01 4 0.021

As can be seen in Table 1, after loading the shelves with the filledcontainers the shelves are firstly kept at a temperature of −35° C. for30 minutes (the “Freezing” phase). Herewith the frozen pellets arebrought to a temperature of −35° C. The pressure is kept atmospheric.Then, the temperature of the shelves is stabilized at −35° C. during 20minutes, pressure is still atmospheric (“Preparation”). Then, thepressure is lowered to 0.370 mbar in a period of ten minutes, thetemperature of the shelves is kept at −35° C. (“Initial sublimation”).Under these conditions, the frozen liquid already sublimates and heat issupplied to the pellets by the two heat sources via conduction andirradiation respectively. However, the speed of sublimation under theseconditions is relatively low. To increase the speed of sublimation, theshelves are brought to a temperature of 40° C. in a period of 3 hours(“Sublimation 1”), and kept at that temperature for 16 hours(“Sublimation 2”). The pressure is kept at the low value of 0.370 mbar.Thereafter, the pressure is further reduced to 0.021 mbar whilst thetemperature of the shelves is brought to 4° C. This latter step takes 1minute (“Closing step”). After that, the sublimation process iscompleted and about 98% of the frozen liquid has left the pellets,thereby transforming into fast-disintegrating tablets. Then, driednitrogen gas with a temperature of about 20° C. is led into thelyophiliser until the pressure is about atmospheric. This takes about 2minutes. Then the door can be opened to take out the tablets. When usingthe present method, it can be seen that a homogenous lyophilising resultcan be obtained, visible as a homogenous bed of lyophilized pellets.After opening the lyophiliser, the tablets are preferably not subjectedto a humid environment to try and prevent condensation of water on thetablets. In particular, the tablets are filled in containers in a closetwith an atmosphere of dried air or nitrogen. After filling thecontainers, they are closed and stored in a cool place (4-8° C.) untilfurther use.

This way, lyophilized spherical tablets can be obtained with an averagediameter of approximately 5% mm and having contained therein a vaccineingredient as shown in Table 2.

TABLE 2 Dose of active component per Pharmaceutical component particle[log¹⁰ EID₅₀] Live Infectious Bronchitis virus, strain 6.6 4-91 Liveinfectious bronchitis virus, 6.5 serotype Massachusetts, Ma5 Liveinfectious bronchitis virus, 6.0 serotype Massachusetts, H120 LiveNewcastle Disease virus 8.5 Live Newcastle Disease virus 9.0

The tablets can be used to provide a pharmaceutical pack. This packconsists of a container (such as a glass or plastic vial) containing oneor more of the tablets and optionally other constituents. The vaccineingredient in the tablets can be administered to an animal as follows.

For the IB tablets, firstly one or more of these tablets arereconstituted in a volume of physiological saline solution, upon whichthe tablets immediately disintegrate (within 60 seconds). The resultingvaccine can be administered to chickens by means of a standardizeddropper into a nostril or eye. For the ND tablets, these can be mixedwith a volume of cool clean water. The resulting vaccine can beadministered to chickens via a spray method or via the drinking water.

Example 2

To obtain tablets containing a chemical drug a plate can be used havingthree rows of cavities according to FIG. 1C. In each of these cavitiesabout 500 μl of fluid formulation is dispensed in approximately 2seconds. At this dosing speed the cavity wall is completely wetted andthus the surface of the part of the pellet that is in the cavity (beforethe pellet is taken out of the cavity) is a negative print of thesurface of the cavity, in this case a smooth surface withoutindentations or wrinkles. If a logo (either positive or negative) wouldhave been present in the cavity, that logo would have been visible onthe surface of the pellet. Examples of fluid formulations which can beused to make frozen pellets are given here-beneath:

Fluid formulation 1: 2 weight percent asenapine((3aS,12bS)-5-Chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrolemaleate (1:1); ORG 5222), 4 weight percent hydrolyzed gelatin (availablefrom Croda, Yorkshire, England), 3 weight percent mannitol (PEARLITOL®,type C160, available from Roquette, Lestrem, France), and water QS(quantum sufficiat, i.e. added to complete 100% total weight).

Fluid formulation 2: 16 weight percent SCH 530348 bisulfate thrombinreceptor antagonist (TRA; see U.S. Pat. No. 7,235,567), 3.5 weightpercent hydrolyzed gelatin, 3 weight percent mannitol, 3.73 weightpercent sodium citrate dihydrate, 1.41 weight percent citric acidmonohydrate, and water QS.

Fluid formulation 3: 8 weight percent TRA, 8 weight percent gelatin (SolP, available from Gelita, Eberbach, Germany), 9 weight percent mannitol,3.73 weight percent sodium citrate dihydrate, 1.41 weight percent citricacid monohydrate, and water QS.

Fluid formulation 4: 8 weight percent TRA, 8 weight percent gelatin (SolP, available from Gelita, Eberbach, Germany), 9 weight percent mannitoland water QS.

The formulation will start to freeze immediately upon contacting thecavity wall. However, it takes approximately 45 seconds before thepellet is substantially frozen such that it can be mechanically handled.After this, the pellets (which have a diameter of approximately 9.8 mm)are pushed out of the cavities (as explained in conjunction with FIGS. 2and 3) and brought over in freeze-dry container 15.

The frozen pellets (having a temperature of about minus 45° C.) arearranged in the container 15 in the form of a densely packed monolayer.Multiple containers are then put in the lyophiliser (see FIG. 5) whichhas beforehand been brought to a temperature of about −35° C. Thelyophiliser is subjected to the following freeze-drye cycle (Table 3).

TABLE 3 Phase Time [h:m] Temp [° C.] Vacuum [mbar] Freezing 00:30 −351000 Preparation 00:30 −35 1000 Initial sublimation, part 1 00:10 −350.310 Initial sublimation, part 2 05:00 −15 0.310 Sublimation 1 07:00 100.310 Sublimation 2 24:00 35 0.310 Closing step 00:01 35 0.310

As described here-above, after the “Closing step”, the sublimationprocess is completed and about 98% of the frozen liquid has left thepellets, thereby transforming into fast-disintegrating tablets. Then,dried nitrogen gas with a temperature of about 20° C. is led into thelyophiliser until the pressure is about atmospheric. This takes about 2minutes. Then the door can be opened to take out the tablets. Thetablets are filled in containers in a closet with an atmosphere of driedair or nitrogen. After filling the containers, they are closed andstored in a cool place (4-8° C.) until further use.

The disintegration of the resulting tablets can be tested by putting atablet in a beaker filled with water having a temperature of 37° C., andmeasuring how long it takes before the tablet is in essence fullydisintegrated (no large pieces visible with the naked human eye). Itappears that all tablets made with the fluid formulations 1, 2, 3 and 4disintegrate within 5-10 seconds.

Example 3

In this example various methods to assess the mechanical stability of atablet are described. The first test is a tablet friability test whichis commonly used for testing the vulnerability of tablets towardsmechanical handling. An apparatus and method to unambiguously asses thisfriability is available from DeltaLab, Moirans of France: the A4113Tablet Friability and Abrasion Tester. Other apparatus and methods arecommercially available as well.

A method for assessing another property that may be used to characterizethe mechanical stability of a tablet is establishing the crushingstrength of a tablet. The principle of this testing method is that astrain is put on a tablet and the resulting force is measured until thetablet is completely crushed. For this a LR5K Plus tensile tester ofLlyod Instruments (Fareham, Hants, UK) can be used. In the presentexample we used the XLC 50N load cell (see FIG. 6). The punchdisplacement (also called “extension”) speed was 10 mm/min.Force-displacement profiles were detected in three-fold and breakagepatterns were determined with Nexygen software which has been suppliedwith the tester. It is noted that as an alternative, the crushingstrength could be measured with the Pharmatest PTB 300/301 (availablefrom Pharmatest, Hainburg, Germany).

In a first experiment a series of 250 μl spherical placebo tablets(containing no medicinal substance) has been made with a method asdescribed here-above (Example 2), differing however in the size of thecavities: the radius is 3.9 mm and the depth is 3.0 mm. Various fluidformulations were used, each comprising a different amount of thegelator Gelita Sol P (Gelita, Eberbach, Germany) and crystalline carriermannitol (PEARLITOL®, type C160, obtained from Roquette, Lestrem,France) to arrive at various different tablets. Apart from thesecompounds the fluid formulations comprised water. In table 5 the variouscompositions are shown.

TABLE 5 Batch gelatin (w %) mannitol (w %) water QS Sol P1 4 3 93 Sol P24 6 90 Sol P3 4 9 87 Sol P4 8 3 89 Sol P5 8 6 86 Sol P6 8 9 83 Sol P7 123 85 Sol P8 12 6 82 Sol P9 12 9 79

When a tablet is being assessed for its crushing strength with the LlyodInstruments LR5K tensile tester, firstly the load is increased with theextension. After some time, when the tablet fails (i.e. breaks), theincrease of the load stops or even decreases. The maximum load at thetime of failure is called the crushing strength. The results of themeasurements of the crushing strengths of the tablets are depicted inTable 6.

TABLE 6 Formulation Average crushing strength (N) Sol P1 0.71 Sol P21.81 Sol P3 2.39 Sol P4 4.11 Sol P5 2.68 Sol P6 4.39 Sol P7 5.89 Sol P84.45 Sol P9 4.19

What can be seen is that the average crushing strength is relativelyhigh for these tablets (which are all based on fluid formulationcomprising 3 or more weight percent of a crystalline carrier and 4 ormore weight percent of a gelator).

In a second experiment a series of 500 μl oblate tablets, optionallycontaining TRA (as mentioned under Example 2) as medicinal substance,has been made with a method as described here-above (Example 2),differing however in the size of the cavities: the radius is 12.0 mm andthe depth is 3.0 mm. Various fluid formulations were used, eachcomprising a different amount of the gelator Gelita Sol P (Gelita,Eberbach, Germany) and crystalline carrier, composed of various amountsof mannitol (PEARLITOL®, type C160, obtained from Roquette, Lestrem,France) and sucrose (α-D-glucopyranosyl-β-D-fructofuranoside). Apartfrom these compounds the fluid formulations comprised water QS. In table7 the various compositions are shown.

TABLE 7 Batch gelatin (w %) mannitol (w %) sucrose (w %) TRA (w %) K 8 92 — L 8 9 4 — M 8 12 2 — N 8 12 4 — O 8 9 2 8 P 8 12 2 8

It appeared that the crushing strength of each of the tablets was thesame, about 5N. This means that the additional sucrose nor the medicinalsubstance have a significant influence on the strength of the tablets inthis experiment. The amount of 8 weight percent gelatin and over 9weight percent mannitol (9 or 12%) therefore, which was found to give avery good crushing strength in the first experiment, appears to be verysuitable for a tablet, in particular for a tablet that needs to have ahigh mechanical stability per se.

Example 4

The propensity of tablets to remain intact after being pressed through afoil has been determined using the device as described in conjunctionwith FIG. 8. This test is referred to as the “push through test” in thisexample. Tablets of different compositions were produced. Amounts andratios of two types of gelatin were varied to obtain a gelator, in linewith data published by Chandrasekhar, R., Hassan, Z., AlHusban, F,Smith, A. M and Mohammed, A. R. Eur. J. Pharm. Biopharm 72 (2009)119-129. Two types of gelatin were used: Sol P (a non gel-forminggelatin) and BS100 (a gel-forming gelatin, i.e. a gelatin that at aconcentration of 4% (w/w) at the dosing temperature of the fluidformulation, forms a gel in the said fluid formulation when left in astationary situation for 24 hours). The latter gelatin is available fromGelita, Eberbach Germany. The amount of mannitol (PEARLITOL®, typeC160), was kept at two levels. All tablets contained 2% (m/v) of a drug,in this case asenapine (see Example 2). Oblate, spherical and flattablets with a volume of 250 μl were made and tested in the push throughtest.

For comparison, a commercially available 250 μl tablet (“Tablet”) wasalso tested. This tablet contained 2% of a drug, 4% of an unknowngelator and 3% mannitol. After testing, tablets were either intact orfractured into numerous pieces, which is illustrated by the schematicdrawings in FIG. 9. Table 8 summarises the results and presents thepercentage of tablets intact when 10 pellets of each composition andspecific shape and volume were tested. It is noted that ODT's are ingeneral so friable that it is commonly understood that no tablets willremain intact in the chosen set-up. Surprisingly however, it was foundthat using the present invention, tablets can be made that remain intactwhen being pressed through a 5 μm thick aluminium foil.

The results in table 8 also imply an effect of the shape of the tabletto survive the push through test. The oblate and spherical shapes ingeneral seem to be superior compared to flat tablets. It is possible toexpress surface curvature relative to the diameter of the unit. Thedosing principle of the method according to the invention, together withthe fact that the liquid dosed has a certain surface tension impliesthat the surfaces of the tablets can be described as two hemispheres inthe case of spherical tablets and two connected spherical caps in thecase of oblate tablets. For reason of the fact that the pellets shrinkduring freeze drying or during storage, or both, the dosing volume isnot an adequate prediction of the future dimensions of the tablets. Itis possible to calculate the radius of curvature of the cap andcorrelate that to the diameter of the tablet using the dimensions of thetablet, using widely available information that correlates dimensions ofa cap with its volume. For example, the relative curvature K of thetablet is defined by the ratio of the radius of curvature (R) of the capand half the diameter of the tablet (D):K=2R/DHigher values of relative curvature are correlated with flattersurfaces. The spheres used in this test had a relative curvature K ofabout 1.0. The oblates had a relative curvature K of about 1.2, and theflat tablets had a relative curvature K of indefinite magnitude. One mayconclude that a value for K between 1 and 1.2 is optimal.

In general, tablets with about 4% gelator seem to have a good resistanceagainst fracture when being pushed through an aluminium foil. It wasalso found that the presence of at least 2 weight percent of agel-forming gelatin (such as BS100) may lead to tablets with a very goodscore in a push through test. This may be due to a higher “network”degree in these tablets. Tablets having a non gel-forming gelatin (suchas Sol P) as additional compound in the gelator are however preferred,due to better disintegration properties.

TABLE 8 Gelatin Sol P BS 100 Mannitol Sample (% w/v) (% w/v) (% w/v)Shape Percentage intact 1 8 0 9 oblate 0 8 0 9 sphere 0 8 0 0 tablet 0 20 4 3 oblate 100 0 4 3 sphere 100 0 4 3 tablet 0 3 3 1 3 oblate 0 4 2 23 oblate 10 2 2 3 sphere 40 2 2 3 tablet 0 5 2 2 8 oblate 40 2 2 8sphere 100 2 2 8 tablet 0 6 1 3 3 oblate 100 1 3 3 sphere 80 1 3 3tablet 0 7 4 0 3 oblate 0 Tablet 4* 3 tablet 0 *type of gelatin notknown

The invention claimed is:
 1. A process for the preparation of afast-disintegrating tablet containing a medicinal substance, comprisingthe steps of: providing a fluid formulation comprising the medicinalsubstance, providing a solid element having formed therein at least onecavity, cooling the solid element to a temperature below a freezingtemperature of the formulation, filling the cavity with the fluidformulation after said cooling, solidifying the formulation whilepresent in the cavity to form a solid pellet comprising the medicinalsubstance without actively shaping the entire surface of the pellet,wherein the volume of the cavity is smaller than 50% of the volume ofthe pellet, taking the pellet out of the cavity, and drying the pelletin a vacuum to obtain the tablet.
 2. A process according to claim 1,characterised in that the formulation is cooled by extracting heat fromthe formulation through a cavity wall by conduction.
 3. A processaccording to claim 2, characterised in that the volume of the pellet islarger than a maximum volume of a free droplet of the fluid formulationat a temperature and pressure used when filling the cavity.
 4. A processaccording to claim 3, characterised in that a speed at which the cavityis filled with the fluid formulation is chosen such that the surface ofthe part of the pellet that is in the cavity before the pellet is takenout of the cavity, is in essence a negative print of the surface of thecavity.
 5. A process according to claim 3, characterised in that across-section of the part of the pellet that is in the cavity is smallerthan a cross-section of the cavity at its entrance.
 6. A processaccording to claim 5, characterised in that the volume of the cavity issmaller than the volume of the pellet.
 7. A process according to claim6, characterised in that a measure is taken to support automaticdetachment of the pellet from the cavity wall.
 8. A process according toclaim 7, wherein the cavity is formed in a solid element characterisedin that the automatic detachment is supported by keeping the temperatureof the solid element adequately beneath the freezing temperature of thefluid formulation.
 9. A process according to claim 8, characterised inthat the pellet is taken out of the cavity by applying a pushing forceto the pellet.
 10. A process according to claim 9, characterised in thatthe pellet is pushed out of the cavity using a tangentially directedforce.
 11. A process according to claim 1, characterised in thatmultiple pellets are placed in a packed bed before the pellets are driedin the vacuum.
 12. A process according to claim 11, characterised inthat the pellets are packed in a heat conducting container having abottom and side walls, and that a heat source is provided above a toplayer of the packed pellets, the heat source having a surface directedto a top layer of the bed, which surface has an emissivity coefficientof at least 0.4, whereafter the pellets are subjected to the vacuumwhile at the same time heating at least the bottom of the container andthe said surface to provide heat to the particles to support drying ofthe pellets.